Are You Confident of the Diagnosis?

Arsenic exposure can occur through environmental or medicinal exposure. A thorough history should be taken to evaluate for possible occupational, environmental, or therapeutic exposure. Arsenicism is a systemic disease that can present with cutaneous, neurologic, and/or gastrointestinal symptoms.

Acute arsenic toxicity most commonly presents with gastrointestinal symptoms with nausea, vomiting, and diarrhea. Edema of the face and eyelids, morbilliform rash, vasomotor disturbances, an asymmetric peripheral neuropathy similar to Guillain-Barré syndrome, and possibly death are other developments associated with acute exposure.

What you should be alert for in the history

Chronic arsenic toxicity can have an extended latency period before signs become evident . Nail changes, cutaneous melanosis, palmar and plantar keratoses, and a history of multiple skin cancers can occur. First signs are often cutaneous changes, with cutaneous melanosis being the earliest sign and palmar and plantar keratoses being the most sensitive marker for arsenic toxicity. Patients may have a history of numerous nonmelanoma skin cancers; ie, squamous cell carcinoma or basal cell carcinoma, with a high occurrence in non-sun exposed areas.

Cutaneous melanosis presents with hyperpigmented bilateral, symmetric macules and patches located on acral, genital, and intertriginous areas. “Raindrop”-like depigmented macules may also occur, and have been likened to “raindrops on a dusty road.”.

Arsenical keratoses are multiple, symmetric, yellow hyperkeratotic papules that range from 0.2-1 cm in size. They are most commonly located on palmar and plantar surfaces, with preference for the thenar and lateral borders of the hands and the base and lateral aspect of the fingers. The keratoses can be found on other areas of friction or trauma on the trunk and extremities.

Expected results of diagnostic studies

Hair and nail analysis can be the most effective diagnostic tool. Hematologic evaluation of arsenic levels is not routinely performed because of its short half life. Urine samples can be collected to measure the concentration of inorganic arsenic in acute arsenic toxicity. Arsenic deposition in hair and nails can begin at approximately 2 weeks of exposure and last for 1-2 years, so this is the recommended test for determination of chronic arsenic exposure . It is recommended to test pubic hairs rather than scalp hairs to eliminate any environmental contamination.A normal arsenic level in nails has been determined to range from 0.02 to 0.5mg/kg. Newer biomarkers that could indicate chronic exposure, like urinary uroporphyrin-III and coproporphyrin-III or blood levels of metallothionein, are being studied.

Histopathology is not specific for arsenic exposure. Arsenical keratoses have compact hyperkeratosis and acanthosis. There is vacuolization of the keratinocytes with varying degrees of dysplasia. Histologic findings can be similar to Bowen's disease (squamous cell carcinoma in situ).

Diagnosis confirmation

The differential diagnosis includes:

Punctate keratosis of the palms and soles. This also presents with yellow, symmetric hyperkeratotic papules of the palms and soles, but differs from arsenical keratosis because when the papule is removed a pit is formed. There is no pit formation with arsenical keratoses.

Verruca vulgaris. Arsenical keratoses differ because the large number of symmetric lesions, the lack of pinpoint bleeding with paring of lesions, and the other associated findings ( ie, cutaneous melanosis and nail changes).

Addison's disease. Hyperpigmentation on pressure points and acral surfaces can also be seen in Addison's disease. This differs from arsenical melanosis because it lacks the depigmented macules, the hyperpigmentation usually involves the mucosa, and this is associated with adrenal insufficiency.

Who is at Risk for Developing this Disease?

Arsenic toxicity is seen in subjects with environmental, occupational, or medicinal exposure. The most common form of environmental exposure is through drinking water, most commonly associated with well water drinking. People living in India, Bangladesh, Argentina, Mexico, Chile, Pakistan, and Taiwan are most at risk of being exposed to toxic levels of arsenic ( >50mg/L).

Groundwater is also used for irrigation of crops for humans and animals, so food imported from these areas are subject to potential arsenic toxicity. Illegally produced “moonshine” has reportedly also been found to contain high levels of arsenic.

Occupational exposure in the US has been associated with pesticides, herbicides, insecticides, and wood additives. Miners are more likely to be exposed, as arsenic is often present with coal, lead, and numerous other elements. Gallium arsenide has been used in the manufacturing of computer microchips and the semiconductor industry.

Use of medications with arsenic, like Fowler's solution, Donovan's solution, and asiatic pills, were previously used to treat leukemia, psoriasis, asthma, pemphigus, pernicious anemia, and Hodgkin's disease. Arsenic trioxide (Trisenox) continues to be used to treat acute myeloid leukemia. Arsenic may also be present in various Chinese or Indian herbal remedies or tonics.

What is the Cause of the Disease?

Etiology

Chronic, cryptic exposure to arsenic, through environmental, occupational, or medicinal means, can lead to the development of the above-mentioned cutaneous changes. There is also believed to be a strong association with development of chromosomal defects that can result in cutaneous neoplasm formation; ie, squamous cell carcinoma, Bowen's disease, and superficial basal cell carcinoma. This has been linked to the trivalent form of inorganic arsenic.

Pathophysiology

The exact mechanism for chromosomal damage has yet to be fully elucidated. Chronic exposure to arsenic is believed to cause DNA damage by generating reactive oxygen species, impairing the methylation and demethylation mechanisms for cellular control, and decreasing the ability of chromosomal excision repair mechanisms to function sufficiently.

Systemic Implications and Complications

It's important to treat squamous cell carcinomas early on to prevent the risk of metastasis. Imaging should be considered if lesions are large ( >2cm) or deep (>2mm in thickness on histology) when diagnosed to rule out metastatic disease. Close follow-up for these high-risk lesions is advised.

In addition to cutaneous lesions, there is also an increased risk of internal malignancies associated with arsenic exposure. Lung, bladder, and kidney malignancies have been the most commonly reported internal neoplasms. Hepatic angiosarcoma and leukemia have also been linked to chronic arsenic exposure. A thorough history and physical examination should be performed and further imaging and workup should be based on these findings.

Cardiovascular disease, peripheral vascular disease, diabetes, reproductive problems and hematologic abnormalities may all result from chronic arsenic exposure. A thorough history and physical should guide further work-up.

Peripheral neuropathy may occur and present similarly to the Guillain-Barré syndrome, with an asymmetric peripheral neuropathy. A neurology consult may be necessary. screening blood work with CBC, liver function, and renal function tests should be ordered.

Treatment Options

SYSTEMIC TREATMENTS

Chelating Agents (for acute toxicity, not likely to be effective once chronic cutaneous signs are visible, as traces of arsenic are not likely to be present )

Optimal Therapeutic Approach for this Disease

For acute arsenic toxicity, the most important treatment is chelation with dimercaprol (BAL) to prevent any further damage. The chelating agent binds to the arsenic ion and allows it to be excreted through the urine. BAL is toxic and has a narrow therapeutic range. It is administered with intramuscular injection.

The dosage recommended for mild arsenic toxicity is 2.5mg/kg four times a day for 2 days, then twice on day 3, and then once daily for 10 days. For severe arsenic toxicity the following dose is recommended: 3mg/kg every 4 hrs for 2 days, then four times on day 3, then twice a day for 10 days.

The potential serious side effects are nephrotoxicity, neutropenia, and hypertension. It is contraindicated in those with hepatic impairment and peanut allergy. Caution is advised in those with G6PD deficiency and hypertension. Pregnancy category C. If prescribed creatinine level should be done at baseline and then monitored during treatment.

Retinoids (ie, acitretin and isotretinoin) have been shown to be a successful therapeutic treatment for arsenical keratosis and the treatment and prevention of cutaneous and internal malignancies associated with chronic arsenic toxicity. They are retinoic acid analogues that are believed to reduce the risk of malignant degeneration and interfere with the survival of the dysplastic keratinocytes.

The recommended initial dose for acitretin and isotretinoin is 0.5-1mg/kg/day. The dosage should be adjusted based on tolerability of side effects. The duration of treatment and need for continuous versus intermittent treatment has yet to be determined. I would favor using isotretinoin in younger woman of child bearing age, because of the shorter half life. Woman of child bearing age should be on oral contraceptives during the course of treatment and for 1 month following as this drug is pregnancy category X.

The most common side effects are cheilitis and xerosis. The most serious side effects include: hyperlipidemia, hepatotoxicity, hyperostosis, pancreatitis, pseudotumor cerebri, and depression. A lipid panel, liver function tests, and creatinine should be checked initially and periodically throughout treatment course. Woman of childbearing age require a monthly pregnancy test.

Physical destruction with cryotherapy or electrodessication have been used to treat arsenical keratoses. Lesions are successfully treated with these methods but are likely to recur and do not prevent new lesions from forming. These methods can result in scarring and potential dysesthesias.

Topicals, such as imiquimod and 5-fluorouracil, have been used to treat arsenical keratoses, although they have not been as successful treating these lesions as they have been at treating superficial skin cancers. These topicals are more effective at treating the superficial basal cell carcinomas and squamous cell carcinomas in situ associated with chronic arsenic exposure.

5-fluourouracil (5-FU) is an anti-metabolite that inhibits thymidylate synthetase, an enzyme necessary for the production of DNA and RNA. Neoplastic cells are known to have an increased rate of mitosis and are preferentially targeted. The disruption of metabolic activity leads to cell death and destruction of dysplastic cells. Imiquimod cream is an immune stimulator that is believed to cause an upregulation of pro-inflammatory cytokines, through Toll-like receptor 7, resulting in cellular apoptosis of dysplastic cells. Recommended application for 5-fluorouracil is two times per day for up to 10-12 weeks for arsenical keratoses.

Imiquimod 5% cream to be applied 3-5 nights per week for about 8 weeks. Treatment course will vary and depend on response rate.

Imiquimod 3.75% cream has not yet been studied for the treatment of arsenical keratoses, but it has been shown to be as effective as imiquimod 5% cream for treating actinic keratoses. Studies are necessary to show if it will show similar success in the treatment of arsenical keratoses and superficial non-melanoma skin cancers associated with arsenic toxicity. The current recommended dosing for actinic keratoses is a daily application for 2 weeks, a 2-week nontreatment period, and then an additional 2-week cycle of daily treatment.

Side effects associated with these treatments are inflammation, oozing, ulceration, crusting, pain, hypo/hyperpigmentation, and treatment failure.

Surgical excision can be performed for arsenical keratoses. Lesions are usually numerous, and surgery does not prevent new lesions from forming or treated keratoses from recurring. I would not recommend this method as first line for treating all keratoses. Surgical excision is a reasonable option for larger symptomatic keratoses, and ones that appear to be evolving into a squamous cell carcinoma.

Surgical excision and Mohs surgery are the first-line treatments for squamous cell carcinoma, Bowen's disease, and basal cell carcinoma that result from chronic arsenic toxicity. Mohs surgery is indicated for neoplasms located on the head and neck, fingers and toes, those over 2 cm, and more aggressive forms of malignancies. Side effects include: bleeding, hematoma, dehiscence, pain, edema, and scar.

Patient Management

Most important is the prevention of arsenic toxicity. Environmental and occupational exposure is not as high in the US as it once was and continues to be in other countries, like India, Bangladesh, and Taiwan. It is important to be careful with herbal remedies and tonics, which are the most likely route of exposure in the US at this time.

If cutaneous signs of arsenic toxicity are identified, it is important to have close follow-up, initially every 3 months, with full body skin checks to monitor closely for the development of skin cancer. It has been shown that subjects with a history of exposure to arsenic can develop squamous cell carcinomas, Bowen's disease, or superficial basal cell carcinomas 15-20 years after their exposure. It is also necessary to have patients follow up with their primary care physicians to monitor for any systemic involvement or development of internal malignancy.

It may be prudent to consider retinoid therapy, despite potential side effects, for chemoprevention, especially if patients have developed a squamous cell carcinoma. If patients opt to use one of the topical chemotherapy or immune-modulating therapies to treat superficial skin cancers, it is important to be compliant with the regimen and if treatment fails, to have the lesion surgically removed.

Unusual Clinical Scenarios to Consider in Patient Management

Good nutrition may be effective at preventing or minimizing the effects of chronic arsenic exposure. Supplementation with selenium, zinc, methionine, vitamin C, and folate have been described.

What is the Evidence?

(This article gives a thorough review of the literature regarding the etiology, epidemiology, and most common clinical presentations of chronic arsenic exposure. It effectively depicts both the present and past causes of worldwide cryptic arsenic exposure, and it clearly points out what changes have been made to try and reconcile these issues.)

(The authors give an in-depth review of the available diagnostic methods and the evidence to support their use. It focuses on the use and reliability of laboratory testing of nails, hair, urine, and blood to determine arsenic exposure levels. Newer methods of testing for biomarkers is presented and the evidence reviewed. The article reports treatment and preventative measures based on a review of the literature.)

(Schwartz's article on arsenic exposure is a review of the historic aspects of exposure, carcinogenesis associated with arsenic exposure, clinical presentation, and treatment options that exist. It uses the literature to present both the cutaneous and internal signs of arsenic exposure, and it stresses the potential for the development of malignancy from chronic toxicity.)

(The authors of this article review the literature on human studies of arsenic toxicity and the different genomic variations that have been identified. They give an in depth review of the literature that focuses on the variations on the cellular level that potentially predispose patients to arsenic induced toxicity.)

(This article reports the results of a small case series performed to evaluate the efficacy of acitretin in the treatment of arsenical keratoses and Bowen's disease. The results showed that acitretin therapy can be successful if the treatment is tolerated at its recommended dose when used for up to 10 months. This case series suggests that retinoids may be used to treat arsenical keratoses and Bowen's disease and as a chemopreventative measure, but stronger evidence is still needed.)

(The article is a case report that shows successful treatment of arsenical keratosis with low dose acitretin and keratolytics. Although the evidence of this report is limited by the size of the case study (1 subject), the authors make reasonable assertions as to why this regimen is successful and should be considered before imiquimod treatment for the treatment of arsenical keratosis.)

(Boonchai reports a case of a patient with chronic arsenic exposure that developed multiple actinic keratoses, basal cell carcinoma, and Bowen's disease that was successfully treated with imiquimod cream. Although the evidence of this report is limited by the size of the case study (1 subject), it suggests that imiquimod cream may be a reasonable option in patients who develop neoplasms due to chronic arsenic toxicity and are not surgical candidates.)

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